Disturbed One-Carbon Metabolism Causing Adverse Reproductive Outcomes in Mice Is Associated with Altered Expression of Apolipoprotein AI and Inflammatory Mediators PPARα, Interferon-ρ, and Interleukin-101,2

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Low dietary choline or deficiency of methylenetetrahydrofolate reductase (Mthfr) leads to hyperhomocysteinemia (Hhcy) and adverse reproductive outcomes. Homocysteine reduces synthesis of ApoAI, the major lipoprotein in HDL-cholesterol; ApoAI is regulated by PPARα and has antiinflammatory properties. Our aim was to determine whether pregnancy complications due to genetic or nutritional deficiencies in 1-carbon metabolism could relate to dysregulation of ApoAI and inflammatory mediators. We fed pregnant mice, with or without a deficiency of Mthfr, control or choline-deficient (ChDD) diets for 10-12 wk and examined levels of ApoAI, PPARα, IFNγ, and IL-10. ApoAI mRNA was reduced in livers of Mthfr+/− mice and ApoAI protein was reduced due to Mthfr deficiency or choline deficiency in liver and plasma. Placental ApoAI protein was also reduced due to Mthfr genotype or choline-deficient diet and in developmentally delayed embryos. Reduced liver PPARα expression (mRNA and protein) was observed in ChDD-fed mice and was associated with increased methylation of a CpG dinucleotide in its promoter. Hepatic IFNγ increased due to genotype, and placental IFNγ was higher in Mthfr+/− ChDD-fed dams compared to Mthfr+/+ mice fed ChDD or Mthfr+/− mice fed CD. IL-10 was reduced in livers of ChDD-fed mice. We propose that a deficiency of dietary choline or Mthfr leads to Hhcy and reduced expression of maternal ApoAI, with reduced ApoAI transfer to embryo. Disturbances in 1-carbon metabolism also reduce maternal PPARa expression, possibly through promoter hypermethylation, and increase IFNγ and decrease IL-10 levels. This disturbance of the T helper (Th1) (IFNγ):Th2 (IL-10) ratio and the increase in inflammatory mediators may contribute to pregnancy complications. J. Nutr. 142: 411-418, 2012.

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